title: Analyses of potential predictive markers and survival data for a response to sunitinib in patients with metastatic renal cell carcinoma.
abstract: BACKGROUND
  Patients with metastatic clear cell renal cell carcinoma (ccRCC) are frequently treated with tyrosine kinase inhibitors (TKI) such as sunitinib. It inhibits angiogenic pathways by mainly targeting the receptors of VEGF and PDGF. In ccRCC, angiogenesis is characterized by the inactivation of the von Hippel-Lindau gene (VHL) which in turn leads to the induction of HIF1α target genes such as CA9 and VEGF. Furthermore, the angiogenic phenotype of ccRCC is also reflected by endothelial markers (CD31, CD34) or other tumor-promoting factors like Ki67 or survivin.
  
  
  METHODS
  Tissue microarrays from primary tumor specimens of 42 patients with metastatic ccRCC under sunitinib therapy were immunohistochemically stained for selected markers related to angiogenesis. The prognostic and predictive potential of theses markers was assessed on the basis of the objective response rate which was evaluated according to the RECIST criteria after 3, 6, 9 months and after last report (12-54 months) of sunitinib treatment. Additionally, VHL copy number and mutation analyses were performed on DNA from cryo-preserved tumor tissues of 20 ccRCC patients.
  
  
  RESULTS
  Immunostaining of HIF-1α, CA9, Ki67, CD31, pVEGFR1, VEGFR1 and -2, pPDGFRα and -β was significantly associated with the sunitinib response after 6 and 9 months as well as last report under therapy. Furthermore, HIF-1α, CA9, CD34, VEGFR1 and -3 and PDGRFα showed significant associations with progression-free survival (PFS) and overall survival (OS). In multivariate Cox proportional hazards regression analyses high CA9 membrane staining and a response after 9 months were independent prognostic factors for longer OS. Frequently observed copy number loss and mutation of VHL gene lead to altered expression of VHL, HIF-1α, CA9, and VEGF.
  
  
  CONCLUSIONS
  Immunoexpression of HIF-1α, CA9, Ki67, CD31, pVEGFR1, VEGFR1 and -2, pPDGFRα and -β in the primary tumors of metastatic ccRCC patients might support the prediction of a good response to sunitinib treatment.
authors.affiliation: Department of Urology, Dresden University of Technology, Dresden, Germany.
authors.forename: Juana
authors.initials: J
authors.lastname: Dornbusch
authors.forename: Aristeidis
authors.initials: A
authors.lastname: Zacharis
authors.forename: Matthias
authors.initials: M
authors.lastname: Meinhardt
authors.forename: Kati
authors.initials: K
authors.lastname: Erdmann
authors.forename: Ingmar
authors.initials: I
authors.lastname: Wolff
authors.forename: Michael
authors.initials: M
authors.lastname: Froehner
authors.forename: Manfred P
authors.initials: MP
authors.lastname: Wirth
authors.forename: Stefan
authors.initials: S
authors.lastname: Zastrow
authors.forename: Susanne
authors.initials: S
authors.lastname: Fuessel
mesh_terms: D020533:Angiogenesis Inhibitors / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D004252:DNA Mutational Analysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D007211:Indoles / Q000627:therapeutic use*; D019394:Ki-67 Antigen / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib; D013997:Time Factors; D046888:Tissue Array Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D019394:Ki-67 Antigen; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011758:Pyrroles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D040281:Vascular Endothelial Growth Factor Receptor-1; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C497446:VHL protein, human; D000077210:Sunitinib